猶他州大學(xué)Huntsman癌癥研究所的研究人員在研究“垃圾DNA(junk DNA)”過(guò)程中,，意外發(fā)現(xiàn)尤文氏肉瘤(Ewing's sarcoma)患者體內(nèi)一種名為GSTM4的蛋白質(zhì)高水平表達(dá)時(shí)，會(huì)抑制化療的效果,。這項(xiàng)研究或許有助于研發(fā)針對(duì)抑制某些患者體內(nèi)GSTM4表達(dá)水平的藥物,。該研究發(fā)表在Oncogene雜志網(wǎng)絡(luò)版上。
尤文氏肉瘤是一種多發(fā)于兒童和青少年的常見(jiàn)骨癌,。在這項(xiàng)研究中,，研究人員的關(guān)注點(diǎn)為尤文氏肉瘤中一種名為EWS-FLI的異常蛋白。他們發(fā)現(xiàn),，EWS-FLI蛋白能引起GSTM4基因總量的增加,，而GSTM4基因在腫瘤中表達(dá)GSTM4蛋白，該蛋白的過(guò)量表達(dá)使得對(duì)該疾病的化療收效甚微,。
該結(jié)果是科學(xué)家研究微衛(wèi)星序列時(shí)發(fā)現(xiàn)的,。微衛(wèi)星序列是基因組中的非編碼序列，因此也被稱為“垃圾DNA”,。通過(guò)檢測(cè)EWS-FLI蛋白與微衛(wèi)星序列之間的相互作用,，研究人員發(fā)現(xiàn)了GSTM4的功能。（生物谷Bioon.com）
生物谷推薦原始出處：
Oncogene 31 August 2009;doi: 10.1038/onc.2009.262
GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance
W Luo1,2, K Gangwal1,2, S Sankar1,2, K M Boucher1, D Thomas3 and S L Lessnick1,2,4
1Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA
2The Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
3Department of Pathology, University of Michigan, Ann Arbor, MI, USA
4Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, UT, USA
Ewing's sarcoma is a malignant bone-associated tumor of children and young adults. Most cases of Ewing's sarcoma express the EWS/FLI fusion protein. EWS/FLI functions as an aberrant ETS-type transcription factor and serves as the master regulator of Ewing's sarcoma-transformed phenotype. We recently showed that EWS/FLI regulates one of its key targets, NR0B1, through a GGAA-microsatellite in its promoter. Whether other critical EWS/FLI targets are also regulated by GGAA-microsatellites was unknown. In this study, we combined transcriptional analysis, whole genome localization data, and RNA interference knockdown to identify glutathione S-transferase M4 (GSTM4) as a critical EWS/FLI target gene in Ewing's sarcoma. We found that EWS/FLI directly binds the GSTM4 promoter, and regulates GSTM4 expression through a GGAA-microsatellite in its promoter. Reduction of GSTM4 levels caused a loss of oncogenic transformation. Furthermore, reduction of GSTM4 resulted in an increased sensitivity of Ewing's sarcoma cells to chemotherapeutic agents, suggesting a role for this protein in drug resistance. Consistent with this hypothesis, patients with Ewing's sarcoma whose tumors had higher levels of GSTM4 expression had worse outcomes than those with lower expression levels. These data show that GSTM4 contributes to the cancerous behavior of Ewing's sarcoma and define a wider role for GGAA-microsatellites in EWS/FLI function than previously appreciated. These data also suggest a novel therapeutic resistance mechanism, in which the central oncogenic abnormality directly regulates a resistance gene.
